Closed Loop/Semi-Closed Loop Therapy Modification System

ABSTRACT

A closed loop/semi-closed loop infusion system provides therapy modification and safeguards against the over-delivery or under-delivery of insulin. A glucose sensor system is configured to obtain a measured blood glucose value. A controller is operationally connected with the glucose sensor system and configured to trigger an alarm based on a measured blood glucose value or amount of insulin delivered, selectively perform calibration of the glucose sensor system when the alarm is triggered, and adjust a therapy delivery parameter when the alarm is triggered, wherein the adjusted therapy delivery parameter is limited to be within a boundary. Thereafter, a delivery system delivers therapy at the adjusted therapy delivery parameter.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 11/739,927, filed Apr. 25, 2007, and entitled “ClosedLoop/Semi-Closed Loop Therapy Modification System,” which is hereinincorporated by reference in its entirety. This application furtherclaims the benefit and right of priority to U.S. provisional applicationSer. No. 60/950,779, filed on Jul. 19, 2007 and U.S. provisionalapplication Ser. No. 60/957,957, filed on Aug. 24, 2007, the contents ofwhich are herein incorporated by reference in their entirety.

FIELD

This invention is directed to infusion systems in closed loop orsemi-closed loop applications and more specifically to systems forcountering the over/under delivery of medication by selectivelyperforming calibration of a glucose sensor system when an alarm istriggered based on a measured blood glucose value or amount of insulindelivered.

BACKGROUND

Diabetes mellitus is the most common of endocrine disorders, and ischaracterized by inadequate insulin action. Diabetes mellitus has twoprincipal variants, known as Type 1 diabetes and Type 2 diabetes. Thelatter is also referred to as DM/II (diabetes mellitus type 2),adult-onset diabetes, maturity-onset diabetes, or NIDDM (non-insulindependent diabetes mellitus).

In the body, most carbohydrates are converted into glucose, which isthen absorbed into the bloodstream. Therefore, eating carbohydratesusually makes blood sugar levels increase. As the glucose levelincreases in the blood, the pancreas releases an insulin hormone.Insulin is necessary to transfer glucose from the blood into the cellsand use the glucose as an energy source in the cells.

However, in people with diabetes, the pancreas does not make enoughinsulin (Type 1 diabetes) or the body cannot respond normally to thereleased insulin (Type 2 diabetes). In both types of diabetes, glucosecannot absorb into the cells normally, thus causing a person's bloodsugar level to increase excessively. Therefore, people with diabetes maykeep track of their carbohydrate intake to be able to expect or predictincreased levels of blood glucose when they have ingested foodscontaining carbohydrates.

Over the years, body characteristics have been determined by obtaining asample of bodily fluid. For example, diabetics often test for bloodglucose levels. Traditional blood glucose determinations have utilized afinger prick method using a lancet to withdraw a small blood sample.These systems are designed to provide data at discrete points but do notprovide continuous data to show variations in the characteristic betweentesting times. These discrete measurements are capable of informing apatient the state of his blood glucose values at a point in time. Thus,the patient has enough information to administer “correction” amounts ofinsulin to reduce his current blood glucose reading. However, thesediscrete readings are not able to provide enough information for anytype of automatic or semi-automatic system of administering insulinbased on blood glucose values.

Recently, a variety of implantable electrochemical sensors have beendeveloped for detecting and/or quantifying specific agents orcompositions in a patient's blood or interstitial fluid. For instance,glucose sensors are being developed for use in obtaining an indicationof blood glucose levels in a diabetic patient. These glucose sensorsconnected (wired or wirelessly) to a blood glucose monitor can providecontinuous glucose readings over a period of time, such as 3 to 5 days.Such readings are useful in monitoring and/or adjusting a treatmentregimen which typically includes the regular administration of insulinto the patient.

Thus, blood glucose readings improve medical therapies withsemi-automated medication infusion pumps of the external type, asgenerally described in U.S. Pat. Nos. 4,562,751; 4,678,408; and4,685,903; or automated implantable medication infusion pumps, asgenerally described in U.S. Pat. No. 4,573,994, which are hereinincorporated by reference. Typical thin film sensors are described incommonly assigned U.S. Pat. Nos. 5,390,671; 5,391,250; 5,482,473; and5,586,553 which are incorporated by reference herein. See also U.S. Pat.No. 5,299,571. In addition, characteristic glucose monitors used toprovide continuous glucose data are described in commonly assigned U.S.patent application Ser. No. 11/322,568 entitled “TelemeteredCharacteristic Monitor System and Method of Using the Same” filed onDec. 30, 2005, which is herein incorporated by reference in itsentirety. In addition, infusion pumps receiving sensor data aredescribed in commonly assigned U.S. patent application Ser. No.10/867,529 entitled “System for Providing Blood Glucose Measurements toan Infusion Device” filed on Oct. 14, 2004, which is herein incorporatedby reference in its entirety.

As sensor technology improves, there is greater desire to use the sensorvalues to control the infusion of drugs and medicine, such as insulin ina closed loop or semi-closed loop system. Specifically, a closed loopsystem for diabetes entails a glucose sensor and an insulin infusionpump attached to a patient, wherein the delivery of insulin isautomatically administered by a controller of the infusion pump based onthe sensor's glucose value readings. A semi-closed system typicallyincludes a patient intervention step, wherein the amount of insulin tobe infused as calculated by the controller of the infusion pump requirespatient acceptance before delivery.

However, given the ramifications of over-delivery and/or under-deliveryof medication, there has yet to be developed a working closedloop/semi-closed loop system that establishes sufficient safeguards forcountering the over-delivery and/or under-delivery of insulin. Inaddition, there has yet to be developed a working closedloop/semi-closed loop system providing robust real-time calibrationadjustment procedures which allows a patient to forgo calibration asneeded.

SUMMARY

According to an embodiment of the invention, a closed loop/semi-closedloop infusion system and method for providing intelligent therapymodification is described. Embodiments of the present invention includetriggering an alarm based on a measured blood glucose value or amount ofinsulin delivered. In preferred embodiments, the method selectivelyperforms calibration of a glucose sensor system when the alarm istriggered, and adjusts a therapy delivery parameter when the alarm istriggered, wherein the adjusted therapy delivery parameter is limited tobe within a boundary. Thereafter, therapy is delivered at the adjustedtherapy delivery parameter.

In one embodiment, the alarm is triggered when the measured bloodglucose value is not consistent with a target blood glucose value.Alternatively, the alarm is triggered when the amount of insulindelivered is not consistent with an expected amount of deliveredinsulin.

In one embodiment, selectively performing calibration of the glucosesensor system includes informing a user that calibration needs to beperformed, prompting the user to decide whether the calibration is to beperformed, performing the calibration if the user decides to perform thecalibration, and proceeding to adjust the therapy delivery parameter ifthe user decides not to perform the calibration.

Preferably, the therapy delivery parameter is adjusted according to adefault basal pattern if the user decides not to perform thecalibration. In one embodiment, adjusting the therapy delivery parametercomprises suspending closed-loop therapy delivery, and reverting toopen-loop therapy delivery using the default basal pattern. Afterward,closed-loop therapy delivery may be resumed if a condition triggeringthe alarm is corrected. Otherwise, open-loop therapy delivery may becontinued if the condition triggering the alarm is not corrected.

Preferably, the method further comprises obtaining a measured bloodglucose value after performing the calibration, and comparing themeasured blood glucose value to a target blood glucose value.Alternatively, the method further comprises determining that acalibrated measured blood glucose value is not consistent with a targetblood glucose value after performing the calibration, and proceeding toadjust the therapy delivery parameter if the calibrated measured bloodglucose value is not consistent with the target blood glucose value. Inone embodiment, the method further comprises proceeding to adjust thetherapy delivery parameter if the user decides to perform thecalibration at a later time.

Preferably, the method further comprises prompting a patient to acceptthe adjusted therapy delivery parameter prior to delivering the therapy.Preferably, the method further comprises performing a safety action ifthe adjusted therapy delivery parameter exceeds the boundary.Preferably, the therapy delivery parameter is a basal rate.

Preferably, the method further comprises logging the adjusted therapydelivery parameter. Preferably, selectively performing calibration ofthe glucose sensor system further comprises obtaining a calibrationvalue from a glucose meter.

In one embodiment, the boundary comprises 25 above or below a presetbasal rate. In another embodiment, the boundary comprises a maximumallowed increase or decrease of a preset basal rate. In an alternativeembodiment, an absolute value of the maximum allowed increase does notequal an absolute value of the maximum allowed decrease.

According to another embodiment of the invention, the system comprises aglucose sensor system and a controller operationally connected with theglucose sensor system. In preferred embodiments, the controller triggersan alarm based on a measured blood glucose value or amount of insulindelivered, selectively performs calibration of the glucose sensor systemwhen the alarm is triggered, and adjusts a therapy delivery parameterwhen the alarm is triggered, wherein the adjusted therapy deliveryparameter is limited to be within a boundary.

Preferably, the system further comprises a delivery system operationallyconnected with the controller and configured to deliver therapy at theadjusted therapy delivery parameter. In one embodiment, the controllertriggers the alarm when the measured blood glucose value is notconsistent with a target blood glucose value. Alternatively, thecontroller triggers the alarm when the amount of insulin delivered isnot consistent with an expected amount of delivered insulin.

In one embodiment, the controller selectively performing calibration ofthe glucose sensor system includes informing a user that calibrationneeds to be performed, prompting the user to decide whether thecalibration is to be performed, performing the calibration if the userdecides to perform the calibration, and proceeding to adjust the therapydelivery parameter if the user decides not to perform the calibration.

Preferably, the controller adjusts the therapy delivery parameteraccording to a default basal pattern if the user decides not to performthe calibration. In one embodiment, the controller adjusts the therapydelivery parameter by suspending closed-loop therapy delivery, andreverting to open-loop therapy delivery using the default basal pattern.Afterward, closed-loop therapy delivery may be resumed if a conditiontriggering the alarm is corrected. Otherwise, open-loop therapy deliverymay be continued if the condition triggering the alarm is not corrected.

Preferably, the controller obtains a measured blood glucose value afterperforming the calibration, and compares the measured blood glucosevalue to a target blood glucose value. Alternatively, the controllerdetermines that a calibrated measured blood glucose value is notconsistent with a target blood glucose value after performing thecalibration, and proceeds to adjust the therapy delivery parameter ifthe calibrated measured blood glucose value is not consistent with thetarget blood glucose value. In one embodiment, the controller proceedsto adjust the therapy delivery parameter if the user decides to performthe calibration at a later time.

Preferably, the controller prompts a patient to accept the adjustedtherapy delivery parameter prior to delivering the therapy. Preferably,the therapy delivery parameter is a basal rate. Preferably, thecontroller logs the adjusted therapy delivery parameter. Preferably,selectively performing calibration of the glucose sensor system furthercomprises obtaining a calibration value from a glucose meter.

In one embodiment, the boundary comprises 25 above or below a presetbasal rate. In another embodiment, the boundary comprises a maximumallowed increase or decrease of a preset basal rate. In an alternativeembodiment, an absolute value of the maximum allowed increase does notequal an absolute value of the maximum allowed decrease.

According to another embodiment of the invention, the system comprisesmeans for triggering an alarm based on a measured blood glucose value oramount of insulin delivered. The system also comprises means forselectively performing calibration of a glucose sensor system when thealarm is triggered, and means for adjusting a therapy delivery parameterwhen the alarm is triggered, wherein the adjusted therapy deliveryparameter is limited to be within a boundary. The system furthercomprises means for delivering therapy at the adjusted therapy deliveryparameter.

Other features and advantages of the invention will become apparent fromthe following detailed description, taken in conjunction with theaccompanying drawings which illustrate, by way of example, variousfeatures of embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

A detailed description of embodiments of the invention will be made withreference to the accompanying drawings, wherein like numerals designatecorresponding parts in the several figures.

FIG. 1 is a block diagram of a closed loop glucose control system inaccordance with an embodiment of the present invention.

FIG. 2 is a front view of a closed loop system located on a body inaccordance with an embodiment of the present invention.

FIG. 3( a) is a perspective view of a glucose sensor system for use inan embodiment of the present invention.

FIG. 3( b) is a side cross-sectional view of the glucose sensor systemof FIG. 3( a).

FIG. 3( c) is a perspective view of a sensor set of the glucose sensorsystem of FIG. 3 (a) for use in an embodiment of the present invention.

FIG. 3( d) is a side cross-sectional view of the sensor set of FIG. 3(c).

FIG. 4 is a cross sectional view of a sensing end of the sensor of FIG.3( d).

FIG. 5 is a perspective view illustrating a preferred embodiment of asubcutaneous sensor insertion set and telemetered characteristic monitortransmitter device when mated together in relation to a characteristicmonitor system.

FIG. 6 is a top view of the subcutaneous sensor insertion set andtelemetered characteristic monitor transmitter device when separated.

FIG. 7 is a top view of an infusion device with a reservoir door in theopen position, for use in an embodiment of the present invention.

FIG. 8 is a side view of an infusion set with the insertion needlepulled out, for use in an embodiment of the present invention.

FIGS. 9( a) and 9(b) are block diagrams of a closed loop glucose controlsystem in accordance with an embodiment of the present invention.

FIG. 10 is a block diagram of auto blood withdrawal and return inaccordance with an embodiment of the present invention.

FIG. 11 is an example of a basal rate profile broken up into three-hourintervals in accordance with an embodiment of the present invention.

FIG. 12 is a flowchart illustrating a method for therapy modification ina closed loop/semi-closed loop infusion system in accordance with anembodiment of the present invention.

FIG. 13 is a flowchart illustrating a method for therapy modification ina closed loop/semi-closed loop infusion system implementing aself-adjusting calibration technique in accordance with an embodiment ofthe present invention.

FIG. 14 is a flowchart illustrating a method for a closed loop systembecoming an open-loop system where patient intervention is required inaccordance with an embodiment of the present invention.

DETAILED DESCRIPTION

As shown in the drawings for purposes of illustration, the invention isembodied in a closed loop/semi-closed infusion system for regulating therate of fluid infusion into a body of a user based on feedback from ananalyte concentration measurement taken from the body. In particularembodiments, the invention is embodied in a control system forregulating the rate of insulin infusion into the body of a user based ona glucose concentration measurement taken from the body.

The system is preferably designed to model a pancreatic beta cell(β-cell). In other words, the system controls an infusion device torelease insulin into a body of a user in a similar concentration profileas would be created by fully functioning human β-cells when respondingto changes in blood glucose concentrations in the body.

Thus, the system simulates the body's natural insulin response to bloodglucose levels and not only makes efficient use of insulin, but alsoaccounts for other bodily functions as well since insulin has bothmetabolic and mitogenic effects. However, algorithms used must model theβ-cells closely. Because the algorithms are designed to minimize glucoseexcursions in the body, without regard for how much insulin isdelivered, the algorithms may cause excessive weight gain, hypertension,and atherosclerosis.

In preferred embodiments of the present invention, the system isintended to emulate the in vivo insulin secretion pattern and to adjustthis pattern consistent with the in vivo β-cell adaptation experiencedby normal healthy individuals. The in vivo β-cell response in subjectswith normal glucose tolerance (NGT), with widely varying insulinsensitivity (S_(I)), is the optimal insulin response for the maintenanceof glucose homeostasis.

The preferred embodiments of the present invention include a glucosesensor system 10, a controller 12 and an insulin delivery system 14, asshown in FIG. 1. The glucose sensor system 10 generates a sensor signal16 representative of blood glucose levels 18 in the body 20, andprovides the sensor signal 16 to the controller 12. The controller 12receives the sensor signal 16 and generates commands 22 that arecommunicated to the insulin delivery system 14. The insulin deliverysystem 14 receives the commands 22 and infuses insulin 24 into the body20 in response to the commands 22. In an alternative semi-closed loopembodiment, the commands 22 would have to be confirmed by the userbefore the insulin delivery system 14 would infuse insulin.

Generally, the glucose sensor system 10 includes a glucose sensor,sensor electrical components to provide power to the sensor and generatethe sensor signal 16, a sensor communication system to carry the sensorsignal 16 to the controller 12, and a sensor system housing for theelectrical components and the sensor communication system.

Typically, the controller 12 includes controller electrical componentsand software to generate commands for the insulin delivery system 14based on the sensor signal 16, and a controller communication system toreceive the sensor signal 16 and carry commands to the insulin deliverysystem 14.

The insulin delivery system 14 preferably includes an infusion deviceand an infusion tube to infuse insulin 24 into the body 20. For example,the infusion device includes infusion electrical components to activatean infusion motor according to the commands 22, an infusioncommunication system to receive the commands 22 from the controller 12,and an infusion device housing to hold the infusion device.

In preferred embodiments, the controller 12 is housed in the infusiondevice housing and the infusion communication system is an electricaltrace or a wire that carries the commands 22 from the controller 12 tothe infusion device. In alternative embodiments, the controller 12 ishoused in the sensor system housing and the sensor communication systemis an electrical trace or a wire that carries the sensor signal 16 fromthe sensor electrical components to the controller electricalcomponents. In other alternative embodiments, the controller 12 has itsown housing or is included in a supplemental device. In anotheralternative embodiment, the controller is located with the infusiondevice and the sensor system all within one housing. In furtheralternative embodiments, the sensor, controller, and/or infusioncommunication systems may utilize a cable, a wire, fiber optic lines,RF, IR, or ultrasonic transmitters and receivers, or the like instead ofthe electrical traces.

FIG. 2 is a front view of a closed loop system located on a body inaccordance with an embodiment of the present invention. Referring toFIG. 2, the closed loop system includes a sensor 26, a sensor set 28, atelemetered characteristic monitor transmitter 30, a sensor cable 32, aninfusion pump 34, an infusion tube 36, and an infusion set 38, all wornon the body 20 of a user. Referring to FIGS. 3( a) and 3(b), thetelemetered characteristic monitor transmitter 30 includes a transmitterhousing 31 that supports a printed circuit board 33, batteries 35,antenna (not shown), and a sensor cable connector (not shown). Referringto FIGS. 3( b), 3(d) and 4, a sensing end 40 of the sensor 26 hasexposed electrodes 42 and is inserted through skin 46 into asubcutaneous tissue 44 of a user's body 20. The electrodes 42 are incontact with interstitial fluid (ISF) that is present throughout thesubcutaneous tissue 44. Referring to FIGS. 3( b) and 3(d), the sensor 26is held in place by the sensor set 28, which is adhesively secured tothe user's skin 46. The sensor set 28 provides for a connector end 27 ofthe sensor 26 to connect to a first end 29 of the sensor cable 32. Asecond end 37 of the sensor cable 32 connects to the transmitter housing31. The batteries 35 included in the transmitter housing 31 providepower for the sensor 26 and electrical components 39 on the printedcircuit board 33. The electrical components 39 sample the sensor signal16 and store digital sensor values (Dsig) in a memory and thenperiodically transmit the digital sensor values Dsig from the memory tothe controller 12, which is included in the infusion device.

As shown in FIGS. 3( a)-3(d), the telemetered characteristic monitortransmitter 30 is coupled to a sensor set 28 by a sensor cable 32. Inalternative embodiments, the cable 32 may be omitted, and thetelemetered characteristic monitor transmitter 30 may include anappropriate connector for direct connection to the connector portion 27of the sensor set 28 or the sensor set 28 may be modified to have theconnector portion 27 positioned at a different location.

For example, FIGS. 5 and 6 show a possible alternative embodiment wherecharacteristic monitor transmitter 500 and the sensor set 510 can bemodified to allow a side-by side direct connection between thecharacteristic monitor transmitter 500 and the sensor set 510 such thatthe characteristic monitor transmitter 500 is detachable from the sensorset 510, as seen in FIG. 6. Another possible embodiment (not shown) canmodify the top of the sensor set 510 to facilitate placement of thetelemetered characteristic monitor transmitter 500 over the sensor set510.

FIG. 7 is a top view of an infusion device with a reservoir door in theopen position, for use in an embodiment of the present invention.Referring to FIGS. 1 and 7, the controller 12 processes the digitalsensor values Dsig and generates commands 22 for the infusion pump 34.Preferably, the infusion device 34 responds to the commands 22 andactuates a plunger 48 that forces insulin 24 out of a reservoir 50located inside the infusion device 34. In particular embodiments, aconnector tip 54 of the reservoir 50 extends through the infusion devicehousing 52 and a first end 51 of the infusion tube 36 is attached to theconnector tip 54. A second end 53 of the infusion tube 36 connects tothe infusion set 38. Referring to FIGS. 2, 7 and 8, insulin 24 is forcedthrough the infusion tube 36 into the infusion set 38 and into the body20. The infusion set 38 is adhesively attached to the user's skin 46. Aspart of the infusion set 38, a cannula 56 extends through the skin 46and terminates in the subcutaneous tissue 44 completing fluidcommunication between the reservoir 50 and the subcutaneous tissue 44 ofthe user's body 20.

In alternative embodiments, the closed-loop/semi-closed loop system canbe a part of a hospital-based glucose management system. Given thatinsulin therapy during intensive care has been shown to dramaticallyimprove wound healing, reduce blood stream infections, renal failure,and polyneuropathy mortality, irrespective of whether subjectspreviously had diabetes, the present invention can be used in thishospital setting to control the blood glucose level of a patient inintensive care.

In these alternative embodiments, since an IV hookup is typicallyimplanted into a patient's arm while the patient is in an intensive caresetting (e.g. ICU), a closed loop glucose control can be establishedwhich piggy-backs off the existing IV connection. Thus, in a hospitalbased system, intravenous (IV) catheters which are directly connected toa patient vascular system for purposes of quickly delivering IV fluids,can also be used to facilitate blood sampling and direct infusion ofsubstances (e.g. insulin, anticoagulants) into the intra-vascular space.Moreover, glucose sensors may be inserted through the IV line to givereal-time glucose levels from the blood stream.

Therefore, depending on the type of hospital based system, thealternative embodiments would not necessarily need the described systemcomponents, such as the sensor 26, the sensor set 28, the telemeteredcharacteristic monitor transmitter 30, the sensor cable 32, the infusiontube 36, and the infusion set 38 as described in the preferredembodiments. Instead, standard blood glucose meters or vascular glucosesensors as described in patent application entitled “Multi-lumenCatheter,” filed Dec. 30, 2002, Ser. No. 10/331,949, which isincorporated by reference herein in its entirety, can be used to providethe blood glucose values to the infusion pump control and the existingIV connection can be used to administer the insulin to the patient.

It is important to appreciate that numerous combinations of devices inthe hospital-based system can be used with the closed loop controller ofthe present invention. FIGS. 9( a) and 9(b) illustrate examples of suchcombinations. Specifically, FIG. 9( a) illustrates a subcutaneous sensorsystem. FIG. 9( b) illustrates an auto blood glucose/intravenous insulininfusion system that can automatically withdraw and analyze blood forglucose concentration at fixed intervals (preferably 5-20 minutes),extrapolate the blood glucose values at a more frequent interval(preferably 1 minute), and use the extrapolated signal for calculatingan IV-insulin infusion according to the controller described below.

The modified auto blood glucose/intravenous insulin infusion systemwould eliminate the need for subcutaneous sensor compensation andsubcutaneous insulin compensation which would be required with asubcutaneous sensor system (as described below when discussing the delayproblems inherent in a subcutaneous sensor system). The automaticwithdrawal of blood, and subsequent glucose determination can beaccomplished with existing technology (e.g. VIA or Biostator like bloodglucose analyzer) or by the system described in FIG. 10.

FIG. 10 is a block diagram of auto blood withdrawal and return inaccordance with an embodiment of the present invention. The system inFIG. 10 uses a peristaltic pump 420 to withdraw blood across anamperometric sensor 410 (the same technology as used in sensor 26) andthen return the blood with added flush (0.5 to 1.0 ml) from thereservoir 400. The flush may comprise of any makeup of saline, heparin,glucose solution and/or the like.

If the blood samples are obtained at intervals longer than 1 minute butless than 20 minutes, the blood glucose determinations can beextrapolated on a minute-to-minute basis with extrapolation based on thepresent (n) and previous values (n-1) to work with the logic of thecontroller as described in detail below. For blood samples obtained atintervals greater than 20 minutes, a zero-order-hold would be used forthe extrapolation. Based on these blood glucose values, the infusiondevice can administer insulin based on the closed loop controllerdescribed in greater detail below.

In other modifications to the system, a manual blood glucose/intravenousinsulin infusion system can be used where frequent manual entries ofblood glucose values from a standard blood glucose meter (e.g., YSI,Beckman, etc) are extrapolated at more frequent intervals (preferably 1min) to create a surrogate signal for calculating IV-insulin infusion.Alternatively, a sensor blood glucose/intravenous insulin infusionsystem can use a continuous glucose sensor (e.g., vascular,subcutaneous, etc.) for frequent blood glucose determination. Moreover,the insulin infusion can be administered subcutaneously rather thanintravenously in any one of the previous examples according to thecontroller described below.

In still further alternative embodiments, the system components may becombined in a smaller or greater number of devices and/or the functionsof each device may be allocated differently to suit the needs of theuser.

Once the hardware for a closed loop/semi-closed loop system isconfigured, such as in the preferred embodiments described above, theaffects of the hardware on a human body are determined by thecontroller. In preferred embodiments, the controller 12 is designed tomodel a pancreatic beta cell (β-cell).

In other words, the controller 12 commands the infusion device 34 torelease insulin 24 into the body 20 at a rate that causes the insulinconcentration in the blood to follow a similar concentration profile aswould be caused by fully functioning human β-cells responding to bloodglucose concentrations in the body 20. Thus, the controller 12 isintended to emulate the in vivo insulin secretion pattern and to adjustthis pattern to be consistent with in vivo β-cell adaptation.

The in vivo β-cell response in subjects with normal glucose tolerance(NGT), with widely varying insulin sensitivity (S_(I)), is the optimalinsulin response for the maintenance of glucose homeostasis. Thebiphasic insulin response of a β-cell can be modeled using components ofa proportional, plus integral, plus derivative (PID) controller alongwith various filters. Description of a PID controller to emulate β-cellscan be found in commonly assigned U.S. Pat. No. 6,558,351, which isincorporated by reference herein in its entirety.

In alternative embodiments, the controller may simply be the controllerin an infusion pump that calculates the amount of insulin to be infusedbased upon the insulin sensitivity/carbohydrate ratio of the individual,the target blood glucose level, amount of carbohydrates to be ingestedand the current blood glucose level supplied by the sensor. An exampleof such a controller is described in commonly assigned U.S. Pat. No.6,554,798 entitled “External Infusion Device with Remote Programming,Bolus Estimator and/or Vibration Alarm Capabilities,” which isincorporated by reference herein in its entirety. In additionalembodiments, the controller may simply be a controller of an infusionpump which takes an additional input of blood glucose values from asensor or meter, where the controller solely relies on the currentglucose value (or predicted glucose value) without relying on additionalfactors such as insulin sensitivity or carbohydrate ratio orcarbohydrates ingested. For example, the system may be used only forovernight closed-loop applications, where there is no expectation of anycarbohydrates ingested. Instead, the key focus may simply be to preventhypoglycemic excursions during sleeping times because the immediaterisks of hypoglycemia are much greater than hyperglycemia. Hypoglycemiacan cause a person to pass out in 15 or 30 minutes while it takes hoursfor the severe effects of hyperglycemia to become evident and causeproblems. In such an application, the controller in the infusion pumpcould simply lower the basal rate or shut off the basal rate completelyto prevent the blood glucose levels from falling to dangerous levels. Onthe other hand, the controller can also correct for hyperglycemicexcursions, by increasing the basal rate simply using only insulinsensitivity factor and current blood glucose value in determining howmuch additional insulin to deliver.

Yet in further embodiments, the system may be a combination closedloop/open loop system. For example, a controller of an infusion pump canbe programmed to go into open loop conditions during meal times (i.e.injections of meal boluses) or correction boluses, where the user willcontrol the amount of insulin given in a bolus. However, the controllerwill place the system back to a default closed-loop/semi-closed systemwhen the insulin on board from a meal or correction bolus is de minimis(for example, 2 hours).

Regardless of the controller used with the present system, closedloop/semi-closed loop algorithms for insulin delivery rely on acontinuous or periodic glucose sensor to drive a control algorithm thatdetermines the optimal insulin dose to administer through a pumpdelivery mechanism. Therefore, sensor reliability and fault detectionand handling are crucial to the dependability and safety of such anapplication.

It is therefore desirable to have an assessment mechanism that canevaluate the sensor signal fidelity and initiate the appropriate actionfollowing detection of a sensor failure. In the event a fault isdetected, a request for sensor replacements should be initiated and atemporary suspension of insulin delivery or control should switch to afixed mode of operation with set basal patterns.

One method of identifying whether the sensor values are reliableinvolves the measure of other signals by the sensor that may provideinformation about the state of the sensor (such as voltage readings,impedance, etc). Another method to assure an accurate sensor reading isto use a dual or 3-up sensing system located in a single sensor site sothat the sensors are used to check one another. Here, the systemcontinues in a closed-loop mode as long as the sensors are in agreementwith each other. Moreover, the likelihood of each sensor failing in thesame way, or at the same time, is small.

A further method for identifying whether the sensor values are reliablerelates to the use of sensor redundancy, wherein the sensing methodand/or sensor location of redundant sensors are different from oneanother. For example, in one embodiment, two subcutaneous sensorslocated at different sites would assure that the potential for commoneffects due to sensor location or interferences is negligible.

However, alternative sites may generate different physiological delaysthat could result from skin temperature or pressure variance at themeasuring site. For example, when additional pressure is applied to oneof the sites due to sleep posture, the readings may vary. Moreover, twoidentical sensors that should exhibit the same readings can exhibitvarying time lags, sensitivities and offsets leading to confusingsignals.

Thus, in further embodiments, sensors using different technology areplaced in different body fluids, e.g. one sensor in subcutaneous tissueand one in blood. Therefore, although the previous description describedvarious types of electro-enzymatic sensors, the system will use othertypes of sensors, such as chemical based, optical based or the like.

For example, other types of sensors are described in the followingreferences: U.S. Provisional Application Serial No. 60/007,515 to VanAntwerp et al. and entitled “Minimally Invasive Chemically AmplifiedOptical Glucose Sensor”; U.S. Pat. No. 6,011,984 issued Jan. 4, 2000 toVan Antwerp et al. and entitled “Detection of Biological Molecules UsingChemical Amplification”; and U.S. Pat. No. 6,766,183 issued Jul. 20,2004 to Walsh et al. and entitled “Long Wave Flourophore SensorCompounds and Other Fluorescent Sensor Compounds in Polymers”, all ofwhich are herein incorporated by reference. Other compounds using DonorAcceptor fluorescent techniques may be used, such as disclosed in U.S.Pat. No. 5,628,310 issued May 13, 1997 to Rao et al. and entitled “Method and Apparatus to Perform Trans-cutaeous Analyte Monitoring”; U.S.Pat. No. 5,342,789 issued Aug. 30, 1994 to Chick et al. and entitled“Method and Device for Detecting and Quantifying Glucose in bodyFluids”; and U.S. Pat. No. 5,246,867 issued Sep. 21, 1993 to Lakowicz etal. and entitled “Determination and Quantification of Saccharides byLuminescent Lifetimes and Energy Transfer”, all of which are hereinincorporated by reference. Hence, use of two different types of sensorsat two different locations, may assure failsafe performance of thesystem that relies heavily on accurate sensor readings.

The insulin delivery system 14 together with the controller 12 mimicsthe delivery of a normal pancreas. To do so, the insulin delivery system14 delivers steady amounts of insulin, known as a basal rate, throughouta day. The basal rate delivers the amount of insulin needed in a fastingstate to maintain target glucose levels. The basal rate insulin isintended to account for the baseline insulin needs of the body, andmakes up approximately fifty percent of the body's total daily insulinrequirements.

Thus, similar to the pancreas, the insulin delivery system 14 deliversbasal rate insulin continuously over the twenty-four hours in the day.The insulin delivery system 14 can be set to automatically provide oneor more different rates during different time intervals of the day.These different basal rates at various time intervals during the dayusually depend on a patient's lifestyle and insulin requirements. Forexample, many insulin delivery system users require a lower basal rateovernight while sleeping and a higher basal rate during the day, orusers may want to lower the basal rate during the time of the day whenthey regularly exercise.

FIG. 11 is an example of a basal rate profile broken up into three-hourintervals in accordance with an embodiment of the present invention.Referring to FIG. 11, the basal pattern 800 can have various basal rates(810, 820, 830, 840) throughout the day, and the basal rates do notnecessarily change at each interval. Moreover, adjustments to thespecific basal rates can be made for each time interval. Notably, theseintervals can be started at any time to match the user's schedule andintervals can be greater or less than three-hours in length. A singlebasal rate interval can be as short as a minimum basal rate intervalcapable of being programmed by an insulin delivery system or have amaximum of 24 hours.

A patient's target blood glucose level (Target) is the amount of bloodglucose (BG) that the patient wishes to achieve and maintain. Typically,a target blood glucose value is between 70-120 mg/dL for preprandial BGand 100-150 mg/dL for postprandial BG. Thus, the patient's basal patternis set to achieve and maintain the Target during insulin therapy.

According to an embodiment of the invention, an algorithm may provideintelligent therapy modifications for various pump therapy parameters tohelp patients more easily achieve and maintain the target blood glucoselevel. The algorithm automatically adjusts insulin delivery parametersbased on the difference between a glycemic target and a measured glucosevalue.

In the preferred embodiments, the algorithm is incorporated in thecontroller 12 that is able to receive signals from the glucose sensorsystem 10. In the preferred embodiments, the algorithm is stored in thecontroller's firmware, but can be stored in a separate software routinein the controller's memory. In addition, the insulin delivery system 14is able to run the algorithm to perform the necessary steps to provideintelligent therapy modifications for various pump therapy parameters.

Alternatively, the algorithm can be run on a separate device such as aPDA, smart phone, computer, or the like. In further alternativeembodiments, the algorithm can be run on the glucose sensor system 10 orcombination glucose sensor system/infusion delivery system or peripheralcontroller.

In preferred embodiments, the intelligent therapy modifications aredisplayed on the insulin delivery system 14, whether the modificationsthemselves were calculated by the controller 12 or sent from anotherdevice either by cable or wireless means. However, in alternativeembodiments, the therapy recommendations can also be given on anyassociated device such as a glucose sensor system display, a handheldPDA, a smart phone, a computer, etc.

Considering a patient's varying body characteristics throughout the day,the patient's insulin requirements may diverge from the patient's presetbasal pattern if blood glucose levels are not as expected. If so, theinsulin delivery system 14 may utilize the control algorithm todetermine an optimal amount of insulin to deliver to the patient.Accordingly, the controller 12 can command the insulin delivery system14 to automatically adjust the basal rate for a given time intervalaccording to the optimal amount determined. Hence, better therapy isprovided because the patient's current insulin requirements areaddressed.

However, when basal rates are allowed to be automatically changed in aclosed loop and/or semi-closed loop system, the insulin delivery system14 is susceptible to delivering too much or too little insulin to thepatient if any devices involved in derivation of the adjusted basal ratefail. For example, if the sensors of the glucose sensor system 10 becomefaulty, then an inaccurate blood glucose level is detected.Consequently, the controller 12 may command the insulin delivery system14 to over-deliver or under-deliver insulin to the patient. Thus,safeguards are preferably implemented to ensure against theover-delivery or under-delivery of insulin. Besides the use of multiplesensors, another (or independently used) possible safeguard may be theuse of a model predictive supervisory control. A separate algorithm canbe used to confirm that blood glucose values are acting as expectedbased on the delivery of insulin. When the actual values deviate toomuch from the predictive models, alarms or other corrective actions canbe used. Examples of model predictive supervisory algorithms can be seenin commonly assigned U.S. patent application Ser. No. 11/700,666entitled “Model Predictive Method and System for Controlling andSupervising Insulin Infusion” filed Jan. 31, 2007. In addition, to theabove mentioned safeguards, the present invention provides for anadditional (or independently used) safety mechanism to avoidover-delivery or under-delivery of insulin.

FIG. 12 illustrates a method for providing therapy modification in aclosed loop/semi-closed loop infusion system, wherein the over-deliveryor under-delivery of insulin is prevented in accordance with thepreferred embodiments of the present invention. Referring to FIG. 12, atthe end of a particular basal pattern time interval, a patient'smeasured blood glucose level is obtained (S500) using the glucose sensorsystem 10 of FIG. 1, for example.

Upon obtaining the measured blood glucose level, the controller 12determines whether the Target is successfully achieved and maintained(S510). If so, the controller commands the insulin delivery system tocontinue delivering insulin to the patient according to the patient'spreset personal basal pattern (S520). However, if the Target is notachieved or maintained, then the controller 12 will attempt to adjustthe basal rate to a temporary adjusted basal rate (S530). Depending onwhether the blood glucose is higher or lower than the targeted bloodglucose level, more or less insulin will be delivered compared to theexisting patient's preset basal rate set in his/her basal pattern.

However, in administering the insulin at the adjusted basal rate, thecontroller 12 preferably limits the adjusted basal rate to a maximumand/or minimum boundary on the adjusted basal rate (S530). The maximumand/or minimum boundary on the adjusted basal rate is set based on thepreset basal rate.

For example, a predefined boundary may be set at 25 above or below thepreset basal rate for any given time interval. In the preferredembodiment, 25 is chosen so that the amount of insulin makes only smallchanges to the blood glucose value over a longer period of time.However, this boundary can be defined at any percentage or value aboveor below a preset basal rate. Therefore, if the adjusted basal rate iswithin 25 above or below the preset basal rate, the controller 12 willcommand the insulin delivery system 14 to deliver insulin at theadjusted basal rate (S550). In a semi-closed system, the insulindelivery system will prompt the patient to accept the adjusted basalrate prior to the delivery of insulin (S540).

Alternatively, if the absolute value of the difference between theadjusted basal rate value and the preset basal rate value is greaterthan a predefined threshold (i.e. exceeds the maximum/minimum boundaryon the preset basal rate), the controller 12 will only adjust thedelivery rate up to the boundary value, and cap the maximum or minimumamount of adjustment allowed compared to the patient's preset basalpattern. If the preset basal pattern has programmed an increase ordecrease at the next time interval (i.e. the time when the basal rate ispreprogrammed to change), the maximum adjustment will move with thechange in the preset basal pattern while maintaining the thresholddifference between the preset basal rate and the adjusted basal rate.

Over time, if the basal rate is regularly adjusted and consistentlyreaches the maximum and/or minimum boundary for any given time interval,this may indicate that the patient's insulin requirements have changed,and therefore the patient's personal basal pattern may need to bealtered. Accordingly, based on the maximum and/or minimum boundary valueconsistently reached during any given time interval, the controller 12may recommend to the patient a new basal rate the patient can integrateinto his/her personal basal pattern.

In alternative embodiments, it is contemplated that systematic errorsmay occur, and therefore the predefined threshold may be exceeded whenadjusting the basal rate (i.e. the amount of insulin to be deliveredexceeds the maximum/minimum boundary on the preset basal rate). In sucha case, the controller does not automatically allow the insulin deliverysystem 14 to deliver insulin to the patient at the adjusted basal rate.Consequently, at least one of a number of actions will be performed(S560).

For example, the adjusted basal rate value can be evaluated for safety.In preferred embodiments, the safety review ensures that the glucosehistory is not too variable for a therapy modification to be made. Atherapy modification should only be made if there is a consistentpattern in blood glucose levels to provide a certain level of confidencein the therapy modification.

In a preferred embodiment, real-time calibration adjustment can beperformed to account for changes in sensor sensitivity during thelifespan of the glucose sensor 26 and to detect when a sensor fails. Anexample of real-time calibration adjustment is described in commonlyassigned U.S. patent application Ser. No. 10/750,978, filed on Dec. 31,2003, entitled “Real Time Self-Adjusting Calibration Algorithm,” whichis a continuation-in-part of U.S. patent application Ser. No.10/141,375, filed on May 8, 2002, entitled “Real Time Self-AdjustingCalibration Algorithm,” now U.S. Pat. No. 6,895,263, which is acontinuation-in-part of U.S. patent application Ser. No. 09/511,580,filed Feb. 23, 2000, entitled “Glucose Monitor Calibration Methods,” nowU.S. Pat. No. 6,424,847, which are all incorporated by reference herein.

FIG. 13 illustrates an additional method for providing therapymodification in a closed loop/semi-closed loop infusion systemimplementing real-time calibration adjustment procedures, wherein theover-delivery or under-delivery of insulin is prevented. Referring toFIG. 13, at the end of a particular basal pattern time interval (or anyother time determined by the controller 12), a patient's measured bloodglucose level is obtained (S600) using the glucose sensor system 10 ofFIG. 1, for example.

Upon obtaining the measure blood glucose level, the controller 12determines whether the Target is successfully achieved and maintained(S610). If so, the controller commands the insulin delivery system tocontinue delivering insulin to the patient according to the patient'spreset personal basal pattern (S620). However, if the Target is notachieved or maintained, then the insulin delivery system must accountfor the possibility that (1) an inaccurate blood glucose level isdetected, (2) that the sensitivity of the glucose sensor 26 is changed,or (3) the glucose sensor 26 is faulty before changing insulin deliveryparameters.

In accordance with the present invention, because the closedloop/semi-closed loop infusion system implements real-time calibrationadjustment procedures, the infusion system may wish to immediatelycalibrate the glucose sensor 26 after determining that the Target is notachieved. However, in some embodiments, the user may not wish toimmediately calibrate the glucose sensor because the user may realizethat the measured blood glucose values are not inaccurate. For example,if the user has recently eaten a meal, the user may expect a rise inblood glucose level because of the ingested meal. Another example is asituation where the user recently exercised and expects to see adecrease in his/her BG value. Accordingly, the blood glucose leveldetected by the glucose sensor system is accurate and not caused by asensor with changed sensitivity or a faulty sensor. As a result, theuser may wish to forgo calibration of the sensor and have the controller12 immediately adjust the basal rate in order to bring the measuredblood glucose level back to the Target range.

In view of the event that a rise in blood glucose level is expected andthe measured blood glucose value is accurate, procedures are needed toallow the user to decide whether the immediate calibration of theglucose sensor is to be performed. In accordance with one embodiment ofthe present invention, if the Target is not achieved and maintained, thecontroller 12 will prompt the user to perform calibration of the glucosesensor (S630). If the user does not wish to perform calibration, orwishes to perform the calibration at a later time, then the controller12 will attempt to adjust the basal rate to a temporary adjusted basalrate (S640). Depending on whether the measured blood glucose level ishigher or lower than the Target, more or less insulin will be deliveredcompared to the existing preset basal rate set in the user's basalpattern.

If the user does wish to perform calibration, the glucose sensor systemwill execute calibration adjustment procedures to calibrate the glucosesensor (S650). Upon completing the calibration adjustment procedures,the user's measured blood glucose level may be obtained. The controller12 can then determine whether the Target is successfully achieved andmaintained (S635). If after completing the calibration adjustmentprocedures, the controller 12 determines that the calibrated measuredblood glucose level is still not within the Target range (S635), thecontroller 12 will adjust the basal rate to a temporary adjusted basalrate (S640). As stated previously, depending on whether the measuredblood glucose level is higher or lower than the Target, more or lessinsulin will be delivered compared to the existing preset basal rate setin the user's basal pattern. On the other hand, if after completing thecalibration adjustment procedures, the controller 12 determines that thecalibrated measured blood glucose level is now within the Target range(S635), the controller 12 will leave the basal rate at the preset basalpattern (S620).

In administering the insulin at the adjusted basal rate, the controller12 preferably limits the adjusted basal rate to a maximum and/or minimumboundary on the adjusted basal rate (S640). The maximum and/or minimumboundary on the adjusted basal rate is set based on the preset basalrate.

For example, a predefined boundary may be set at 25 above or below thepreset basal rate for any given time interval. In the preferredembodiment, 25 is chosen so that the amount of insulin makes only smallchanges to the blood glucose value over a longer period of time.However, this boundary can be defined at any percentage or value aboveor below a preset basal rate. Therefore, if the adjusted basal rate iswithin 25 above or below the preset basal rate, the controller 12 willcommand the insulin delivery system 14 to deliver insulin at theadjusted basal rate (S670). In a semi-closed system, the insulindelivery system will prompt the patient to accept the adjusted basalrate prior to the delivery of insulin (S660).

Alternatively, if the absolute value of the difference between theadjusted basal rate value and the preset basal rate value is greaterthan a predefined threshold (i.e. exceeds the maximum/minimum boundaryon the preset basal rate), the controller 12 will only adjust thedelivery rate up to the boundary value, and cap the maximum or minimumamount of adjustment allowed compared to the patient's preset basalpattern. If the preset basal pattern has programmed an increase ordecrease at the next time interval (i.e. the time when the basal rate ispreprogrammed to change), the maximum adjustment will move with thechange in the preset basal pattern while maintaining the thresholddifference between the preset basal rate and the adjusted basal rate.

Over time, if the basal rate is regularly adjusted and consistentlyreaches the maximum and/or minimum boundary for any given time interval,this may indicate that the patient's insulin requirements have changed,and therefore the patient's personal basal pattern may need to bealtered. Accordingly, based on the maximum and/or minimum boundary valueconsistently reached during any given time interval, the controller 12may recommend to the patient a new basal rate the patient can integrateinto his/her personal basal pattern.

In alternative embodiments, it is contemplated that systematic errorsmay occur, and therefore the predefined threshold may be exceeded whenadjusting the basal rate (i.e. the amount of insulin to be deliveredexceeds the maximum/minimum boundary on the preset basal rate). In sucha case, the controller does not automatically allow the insulin deliverysystem 14 to deliver insulin to the patient at the adjusted basal rate.Consequently, at least one of a number of actions will be performed(S680).

For example, the adjusted basal rate value can be evaluated for safety.In preferred embodiments, the safety review ensures that the glucosehistory is not too variable for a therapy modification to be made. Atherapy modification should only be made if there is a consistentpattern in blood glucose levels to provide a certain level of confidencein the therapy modification.

In accordance with the present invention, the control algorithm maydetermine the variability of the glucose history by using a standarddeviation of a cluster of the most recent data. The standard deviationis compared against the difference between an average blood glucosevalue and the target blood glucose value. If the glucose history is toovariable for a therapy modification to be made, i.e. the standarddeviation is greater than the difference between the average bloodglucose value and the target blood glucose value, no therapymodification is made.

In alternative embodiments, the safety check is only applied forincreases in the basal rate because the immediate risks of hypoglycemiaare much greater than hyperglycemia. Hypoglycemia can cause a person topass out in 15 to 30 minutes while it takes hours for the severe effectsof hyperglycemia to become evident and cause problems.

In another example, if the absolute value of the difference between theadjusted basal rate value and the preset basal rate value is greaterthan the predefined threshold, the insulin delivery system 14 willnotify the patient that the predefined threshold has been exceeded. Thismay be accomplished visually by informing the patient of the eventthrough a display screen on the insulin delivery system, or by settingoff different alarms via audio or vibration.

During notification, the patient may be prompted to either accept theinsulin delivery at the adjusted basal rate or asked to manually input abasal rate within the predefined threshold. Additionally, duringnotification, the patient may be also be asked to perform a bloodglucose strip meter reading to confirm whether the measured bloodglucose values read by the glucose sensor system are accurate.

In preferred embodiments, all obtained and measured glucose values andbasal rates adjusted during a basal pattern are logged. Accordingly, apatient can refer to the log to manage treatment more accurately. Forexample, the patient can utilize the log to assess where to modify thepatient's personal basal pattern during a certain period of time.Moreover, as certain patterns of automatic increase and decrease ofbasal rates occur, the controller and the insulin delivery system canutilize the log to provide therapy recommendations to the patient formodifying the patient's personal pattern.

In addition to these safeguards, in preferred embodiments, there will bea safeguard that the closed-loop system will fall out of a closed-loopalgorithm if certain alarms are triggered. FIG. 14 describes anembodiment of the invention where the closed-loop algorithm will turninto an open-loop system where patient intervention is required. Asassumed in S700, the system is running in closed-loop mode. Thus, thedelivery system is controlled automatically based on sensor readings.S710 describes that a default basal pattern can be updated periodicallyas the closed-loop system is run. Preferably, the default basal patternis adjusted based on a true basal delivery history, as opposed todefault preset values. Thus, the default basal patterns can be updated.Updates can be done automatically or be required to have user approval.

At S720, an event is triggered that requires the system to drop out ofclosed-loop control. This may be triggered by any of the previouslymentioned safety features built into the closed-loop control. Since thetransition from closed-loop to open-loop is itself a backup safetyfeature, the specific triggers can be adjusted to balance the need forsafety versus unnecessarily falling out of closed-loop control. At S730,when the closed-loop control reverts into open-loop control, inpreferred embodiments, the basal delivery will use the latest updateddefault basal patterns as described with respect to S720 to continue todeliver the necessary basal dose of insulin. However, in alternativeembodiments, the open-loop system may simply revert back to the originaldefault basal patterns. At S740, the logic returns to closed-loopcontrol if the error has been corrected (S750) or will continue inopen-loop delivery mode (S760).

In accordance with another embodiment of the present invention, theclosed loop/semi-closed loop infusion system accounts for a patient'sinsulin on board (IOB) when providing safeguards. IOB is insulin that apatient has taken but has yet to metabolize. Generally, insulin actionin the patient's body occurs slowly over time. Therefore, when a patienttakes insulin via a correction bolus, for example, the correction bolusrequires time to act. Accordingly, in certain circumstances, because ofthe delayed insulin action, the glucose sensor system may measure a highpatient blood glucose level and compel the controller to deliverunneeded insulin to the patient.

To prevent “over-stacking” or the over-delivery of insulin, algorithmsaccounting for IOB may be programmed into the infusion system to takeinto consideration the delayed insulin action. Moreover, the algorithmsmay compare an IOB value expected as a result of a patient followingnormal open-loop pump therapy to an actual IOB value arising from thepatient following bolus recommendations from the infusion system.Preferably, the algorithms may consider a preprogrammed tolerance, suchas 50 above or below the expected IOB value, for differences between theexpected IOB and the actual IOB. Preferably, as long as the actual IOBvalue stays within the preprogrammed tolerance (i.e. permissive IOB),the infusion system will know that insulin action is delayed, and willnot trigger an alarm or automatically deliver more insulin due to anelevated glucose level in the patient.

In accordance with the present invention, because delayed insulin actioncauses the glucose sensor system to measure a high patient blood glucoselevel, the infusion system may deduce that a glucose sensor is faulty.However, by utilizing the concept of permissive IOB the delayed insulinaction is taken into consideration by the infusion system, and will notalert the patient to replace the sensor unless insulin delivery becomesunreasonable. For example, a sensor would not be flagged for removalunless insulin delivery is sufficiently out of range, such as when theactual IOB value is beyond 50 above or below the expected IOB value.Conversely, even if blood glucose levels indicated by the glucose sensorseem to indicate that the current blood glucose levels are within aboundary of the targeted blood glucose, an unusual amount of insulindelivery (e.g. amount of actual IOB is much higher/lower than theexpected IOB), an alarm can be triggered and/or safety procedures can beadopted as described above.

In accordance with another embodiment of the present invention, a modelsupervisory system may be implemented by the infusion system. The modelsupervisory system may use metabolic models such as a virtual patientmodel. Using the model, an expected glucose level can be calculatedbased on a past history of meals and insulin delivery and value comparedto a current sensor glucose value. Similar to how a tolerance intervalis placed around a permissible IOB, a tolerance interval may be placedaround a model predicted glucose level. Accordingly, the supervisorymodel may be able to detect not only sensor error, but catheter problemsas well.

While the description above refers to particular embodiments of thepresent invention, it will be understood that many modifications may bemade without departing from the spirit thereof. Thus, the accompanyingclaims are intended to cover such modifications as would fall within thetrue scope and spirit of the present invention.

The presently disclosed embodiments are therefore to be considered inall respects as illustrative and not restrictive, the scope of theinvention being indicated by the appended claims, rather than theforegoing description, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

1-38. (canceled)
 39. A method for providing therapy modification in aninfusion system, the method comprising: delivering insulin at a currentbasal rate in an existing basal pattern for a user; obtaining aplurality of measured blood glucose values including a current measuredblood glucose value and historical measured blood glucose values;triggering an alarm when the current measured blood glucose value ishigher or lower than a target blood glucose value; informing the userthat calibration of a glucose sensor system needs to be performed whenthe alarm is triggered; prompting the user to decide whether thecalibration is to be performed; performing the calibration if the userdecides to perform the calibration; determining a basal rate adjustmentfrom the current basal rate to an adjusted basal rate if the userdecides not to perform the calibration in order to bring the currentmeasured blood glucose value to be consistent with the target bloodglucose value, wherein the basal rate adjustment is limited to be withina boundary based on the current basal rate; and delivering insulin atthe adjusted basal rate if the basal rate adjustment is within theboundary.
 40. The method of claim 39, further comprising: prior todelivering insulin at the adjusted basal rate, evaluating whether acondition is safe to deliver insulin at the adjusted basal rate.
 41. Themethod of claim 40, wherein evaluating whether a condition is safe todeliver insulin at the adjusted basal rate comprises determining thatthe condition is unsafe if the basal rate adjustment exceeds theboundary, and the method further comprises: prompting the user to acceptthe adjusted basal rate; and delivering insulin at the adjusted basalrate.
 42. The method of claim 40, wherein evaluating whether a conditionis safe to deliver insulin at the adjusted basal rate comprisesdetermining that the condition is unsafe if the plurality of measuredblood glucose values do not follow a consistent pattern, and the methodfurther comprises: continuing delivery of insulin at the current basalrate if the condition is unsafe.
 43. The method of claim 40, furthercomprising: suspending closed-loop delivery of insulin if the conditionis unsafe; and reverting to open-loop delivery of insulin using adefault basal pattern.
 44. The method of claim 43, further comprising:resuming closed-loop delivery of insulin if the unsafe condition iscorrected; and continuing open-loop delivery of insulin if the unsafecondition is not corrected.
 45. The method of claim 39, wherein theboundary comprises a percentage of the current basal rate above or belowthe current basal rate.
 46. The method of claim 39, wherein the boundarycomprises a maximum allowed increase or decrease of the current basalrate.
 47. The method of claim 39, further comprising: after performingthe calibration, obtaining a new measured blood glucose value; comparingthe new measured blood glucose value to the target blood glucose value;determining whether the new measured blood glucose value is higher orlower than the target blood glucose value; determining a second basalrate adjustment from the current basal rate to a second adjusted basalrate if the new measured blood glucose value is higher or lower than thetarget blood glucose value in order to bring the new measured bloodglucose value to be consistent with the target blood glucose value,wherein the second basal rate adjustment is limited to be within theboundary based on the current basal rate; and delivering insulin at thesecond adjusted basal rate if the second basal rate adjustment is withinthe boundary.
 48. The method of claim 39, further comprising logging theadjusted basal rate.
 49. An infusion system for providing therapymodification, the system comprising: a glucose sensor system; a deliverysystem configured to deliver insulin into a user; and a controlleroperationally connected with the glucose sensor system and the deliverysystem, wherein the controller causes the delivery system to deliverinsulin at a current basal rate in an existing basal pattern for theuser, obtains a plurality of measured blood glucose values including acurrent measured blood glucose value and historical measured bloodglucose values, triggers an alarm when the current measured bloodglucose value is higher or lower than a target blood glucose value,informs the user that calibration of the glucose sensor system needs tobe performed when the alarm is triggered, prompts the user to decidewhether the calibration is to be performed, performs the calibration ifthe user decides to perform the calibration, determines a basal rateadjustment from the current basal rate to an adjusted basal rate if theuser decides not to perform the calibration in order to bring thecurrent measured blood glucose value to be consistent with the targetblood glucose value, wherein the basal rate adjustment is limited to bewithin a boundary based on the current basal rate, and causes thedelivery system to deliver insulin at the adjusted basal rate if thebasal rate adjustment is within the boundary.
 50. The system of claim49, wherein the controller further evaluates whether a condition is safeto deliver insulin at the adjusted basal rate prior to the deliverysystem delivering insulin at the adjusted basal rate.
 51. The system ofclaim 50, wherein the controller evaluates whether a condition is safeto deliver insulin at the adjusted basal rate by determining that thecondition is unsafe if the basal rate adjustment exceeds the boundary,and the controller further prompts the user to accept the adjusted basalrate, and causes the delivery system to deliver insulin at the adjustedbasal rate.
 52. The system of claim 50, wherein the controller evaluateswhether a condition is safe to deliver insulin at the adjusted basalrate by determining that the condition is unsafe if the plurality ofmeasured blood glucose values do not follow a consistent pattern, andthe controller further causes the delivery system to continue deliveryof insulin at the current basal rate if the condition is unsafe.
 53. Thesystem of claim 50, wherein the controller further causes the deliverysystem to suspend closed-loop delivery of insulin if the condition isunsafe, and revert to open-loop delivery of insulin using a defaultbasal pattern.
 54. The system of claim 53, wherein the controllerfurther causes the delivery system to resume closed-loop delivery ofinsulin if the unsafe condition is corrected, and continue open-loopdelivery of insulin if the unsafe condition is not corrected.
 55. Thesystem of claim 49, wherein the boundary comprises a percentage of thecurrent basal rate above or below the current basal rate.
 56. The systemof claim 49, wherein the boundary comprises a maximum allowed increaseor decrease of the current basal rate.
 57. The system of claim 49,wherein after performing the calibration, the controller further obtainsa new measured blood glucose value, compares the new measured bloodglucose value to the target blood glucose value, determines whether thenew measured blood glucose value is higher or lower than the targetblood glucose value, determines a second basal rate adjustment from thecurrent basal rate to a second adjusted basal rate if the new measuredblood glucose value is higher or lower than the target blood glucosevalue in order to bring the new measured blood glucose value to beconsistent with the target blood glucose value, wherein the second basalrate adjustment is limited to be within the boundary based on thecurrent basal rate, and causes the delivery system to deliver insulin atthe second adjusted basal rate if the second basal rate adjustment iswithin the boundary.
 58. The system of claim 49, wherein the controllerfurther logs the adjusted basal rate.